Schizophrenia is a multigenic disorder where each genetic mutation contributes to subsets of the behavioral phenotypes prototypical of the disease. In order to test the hypothesis that a particular mutation contributes to schizophrenia it is essential to associate alterations in neuronal function caused by gene mutations with specific behavioral phenotypes. Here we propose to study functionally the molecular basis for olfactory dysfunction, a sensory phenotype found in a substantial fraction of schizophrenics. We hypothesize that a mutation in the promoter for the alpha7 nicotinic acetylcholine receptor contributes to diminished ability to differentiate between closely related odorants by a substantial number of schizophrenics. We show that we can study olfactory bulb neurons in humans, not only using neuroantomical techniques, but also by utilizing neuronal cultures from postmortem tissue, and we present preliminary feasibility data showing we can record nicotinic responses in these cells utilizing calcium imaging techniques. Using human olfactory bulb neurons in culture, we propose to test the hypothesis that alterations in the alpha7 nicotinic receptor promoter causes functional changes in the responses of olfactory bulb interneurons to acetylcholine that contribute to olfactory dysfunction in schizophrenics. Parallel experiments in congenic and knockout mice with altered expression of the alpha7 acetylcholine receptor will test the link between altered responsiveness to acetylcholine and olfactory behavior. These experiments will be the first to study neuronal function in schizophrenics and controls.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
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Special Emphasis Panel (ZMH1)
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University of Colorado Denver
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